Defects in the mitochondrial respiratory complexes cause a number of metabolic diseases and are believed to play pivotal roles in the pathogenesis of age-related neurodegenerative disorders. Our laboratory's long term goal is to understand the biology of these conditions and develop effective treatments. To achieve these goals we have developed mouse models with defects in different mitochondrial respiratory complexes. We now propose to study the pathogenic mechanisms associated with defects in specific mitochondrial respiratory complexes (complexes I, III or IV). Our preliminary data showed some remarkable differences in the phenotypes depending on the complex affected. The identification of metabolic signatures of brains affected by the different defects will be used to better understand the pathogenic mechanisms. Finally, based on the information gathered in the first two aims, we will test whether increases in mitochondrial biogenesis and lipid utilization can have a protective effect for certain mitochondrial encephalopathies. PUBLIC HEALTH RELEVANCE: Defects in mitochondrial respiratory complexes have been associated with many metabolic diseases. There is a great deal of variation in the clinical manifestations of these defects, but the reason for this is not known. We propose to study mouse models with defects in the respiratory complexes I, III and IV to better define the mechanisms responsible for the different clinical presentations. We will define metabolic signatures of deficient brains and use this information to fine tune therapeutic approaches based on an increase in mitochondrial biogenesis.